•Fig. 43.16 Themineralocorticoidreceptor(MR)isprotectedfromactivationbycortisolbytheenzyme11β-hydroxysteroiddehydrogenasetype2(11β-HSD2),whichconvertscortisoltoinactivecortisone.Cortisonecanbeconvertedbacktocortisolinglucocorticoidtargetcellsbytheenzyme11β-HSDtype1.GRE,glucocorticoidresponseelement;GTF,generaltranscriptionfactors;MRE,mineralocorticoidresponseelement.(ModifiedfromWhiteBA,PorterfieldSP.Endocrine and Reproductive Physiology. 4thed.Philadelphia:Mosby;2013.)Aldosterone Aldosterone 11˜-HSD2 MR-chaperone complex Dissociated chaperones Dissociated chaperonesMR-aldosterone complex Mineralocorticoid-specific biological response Glucocorticoid-specific biological response Mineralocorticoid target cell 11˜-HSD1 Glucocorticoid target cell • Dimerization • Nuclear transport • Binding to MREs • Recruitment of coactivator proteins and GTFs • Altered transcription of aldosterone-regulated genes • Dimerization • Nuclear transport • Binding to GREs • Recruitment of coactivator proteins and GTFs • Altered transcription of cortisol-regulated genes Cortisol Cortisol Cortisol GR-chaperone complex GR-cortisol complex Cortisone Cortisone Cortisone Blood
Adrenocortical hormone excess istermedCushing’s syndrome. Pharmacological useofexogenouscorticosteroidsisnowthemostcommoncauseofCushing’ssyndrome.ThenextmostprevalentcauseisACTH-secreting tumors. TheformofCushing’ssyndromecausedbyafunctionalpituitaryadenomaiscalledCushing’s disease. ThefourthmostcommoncauseofCushing’ssyndromeisprimary hypercortisolism resultingfromafunctionaladrenaltumor.Ifthedisorderisprimaryorifitisaresultofcorticosteroidtreatment,secretionofACTHwillbesuppressedandincreasedskinpigmentationwillnotoccur.However,ifhypersecretionoftheadrenalistheresultofanACTH-secretingnonpituitarytumor,ACTHlevelssometimesbecomehighenoughtoincreaseskinpigmentation.
Increasedcortisolsecretioncausesweightgainwithacharacteristiccentripetalfatdistributionanda“buffalohump.”
Thefaceappearsrounded(fatdeposition),andthecheeksmaybereddened,inpartbecauseofthepolycythemia.Thelimbsarethinowingtoskeletalmusclewasting(fromincreasedproteolysis),andmuscleweaknessisevident(frommuscleproteolysisandhypokalemia).Proximalmuscleweaknessisapparent,sothepatientmayhavedifficultyclimbingstairsorrisingfromasittingposition.Theabdominalfataccumulationcoupledwithatrophyoftheabdominalmusclesandthinningoftheskinproducesalargeprotrudingabdomen.Purpleabdominalstriaeareseenasaresultofdamagetotheskinbytheprolongedproteolysis,increasedintraabdominalfat,andlossofabdominalmuscletone.Capillaryfragilityoccursbecauseofdamagetotheconnectivetissuesupportingthecapillaries.Patientsarelikelytoshowsignsofosteoporosisandpoorwoundhealing.Theyhavemetabolicdisturbancesthatincludeglucoseintolerance,hyperglycemia,andinsulinresistance(see